The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.
PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Although it is a complex process influenced by both physiological and psychological factors and is always subjective, its causes or syndromes can be classified. Some of the most relevant pain subtypes are neuropathic pain, allodynia, hyperalgesia, and peripheral neuropathy.
Over twenty million patients have surgical procedures each year. Postsurgical pain (interchangeably termed, post-incisional pain), or pain that occurs after surgery or traumatic injury, is a serious and often intractable medical problem. Pain is usually localized within the vicinity of the surgical site. Post-surgical pain can have two clinically important aspects, namely resting pain, or pain that occurs when the patient is not moving and mechanical pain which is exacerbated by movement (coughing/sneezing, getting out of bed, physiotherapy, etc.). The major problem with post-surgical pain management for major surgery is that the drugs currently used have a variety of prominent side effects that delay recovery, prolong hospitalization and subject certain vulnerable patient groups to the risk of serious complications.
The three major classes of pharmaceutical drugs used to treat post-surgical pain are the opioid analgesics, local anaesthetics, and the non-steroidal anti-inflammatory drugs (NSAID). Two of these classes of drugs, the opioid analgesics and NSAIDs, are typically administered systemically while the local anaesthetics (e.g. channel blockers) are administered non-systemically during surgery.
The systemic administration of drugs to relieve pain after surgery is frequently inadequate. For example, systemic administration of opioids after surgery may cause nausea, the inhibition of bowel function, urinary retention, inhibition of pulmonary function, cardiovascular effects, and sedation.
“Post-surgical pain” is interchangeable with “post-incisional” or “posttraumatic pain” and refers to pain arising or resulting from an external trauma such as a cut, puncture, incision, tear, or wound into tissue of an individual (including those that arise from all surgical procedures, whether invasive or non-invasive), i.e. to pain developed as a consequence of surgery. As used herein, “post-surgical pain” does not include pain that occurs without an external physical trauma. In some embodiments, post-surgical pain is internal or external pain, and the wound, cut, trauma, tear or incision may occur accidentally (as with a traumatic wound) or deliberately (as with a surgical incision). As used herein, “pain” includes nociception and the sensation of pain, and pain can be assessed objectively and subjectively, using pain scores and other methods, e.g., with protocols well-known in the art. Post-surgical pain, as used herein, includes allodynia (i.e., pain due to a stimulus that does not normally provoke pain) and hyperalgesia (i.e., increased response to a stimulus that is normally painful), which can in turn, be thermal or mechanical (tactile) in nature. Therefore, the pain is characterized by thermal sensitivity, mechanical sensitivity and/or resting pain (e.g. persistent pain in the absence of external stimuli). Further, the pain can be primary (e.g., resulting directly from the pain-causing event) or secondary pain (e.g., pain associated with, but not directly resulting, from the pain-causing event).
Different animal models and studies on postoperative incisional pain the same are reported in the state of the art (T. J. Brennan et al. Pain 1996, 64, 493-501; P. K. Zahn et al. Regional Anaesthesia and Pain Medicine 2002, Vol. 27, No 5 (September-October), 514-516).
Opioids and opiates are potent analgesics widely used in clinical practice. Opioid and opiates drugs are classified typically by their binding selectivity in respect of the cellular and differentiated tissue receptors to which specific drug specie binds as a ligand. These receptors include mu (μ), delta (δ), kappa (κ) and the nociceptive receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opioid mu receptors. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. However, despite their good activity as analgesics, opioids and opiates have the drawback of causing dependence.
Sigma receptors are non-opiaceous type of receptors of great interest in pharmacology due to their role in analgesia related processes. The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol. The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-1) site, and has micromolar affinity for the sigma 2 (σ-2) site. Haloperidol has similar affinities for both subtypes.
It has been reported that some sigma ligands in combination with opioids or opiates are capable of modulating the analgesic effect thereof. It is known, for example, that haloperidol potentiates the activity of different opioids and opiates such as morphine, DADL or bremazocine [Chichenkov, O. N. et al: Effect of haloperidol on the analgesic activity of intracisternally and intrathecally injected opiate agonists, Farmakologiya i Toksikologiya (Moscow) (1985), 48(4), 58-61]. Chien C. et al. also referred the synergistic effect of the combination of haloperidol and morphine [Selective antagonism of opioid analgesia by a sigma system, J Pharmacol Exp Ther (1994), 271, 1583-1590 and Sigma antagonists potentiate opioid analgesia in rats, Neurosci Lett (1995), 190, 137-139] and Marazzo A. et al taught the capacity of the sigma ligand (+)-MR200 to modulate K-opioid receptor mediated analgesia. Mei J. et al confirmed the importance of sigma-1 receptors as a modulatory system on the analgesic activity of opioid drugs [Sigmal receptor modulation of opioid analgesia in the mouse, J Pharmacol Exp Ther (2002), 300(3), 1070-1074]. Notwithstanding, in all of this cases the problem of dependence induced by opioids and opiates remain to be present.
One of the pharmacological approaches to solve the problem of opioid and opiate dependence has been the co-administration of opioids or opiates and sigma ligands. For instance, sigma-1 receptor agonist SA4503 has been shown to have a modulatory effect on addiction to morphine [Nomura, M. et al: Studies on drug dependence (Rept. 322): Attenuation of morphine- and psychostimulants-induced place preference by sigmal receptor agonist SA4503, 72nd Annual Meeting of the Japanese Pharmacological Society (Sapporo, Japan-March 1999)]. Also, sigma-1 agonist DHEA has shown some capacity to attenuate the development of morphine dependence [Noda, Y. et al: A neuroactive steroid, dehydroepiandrosterone sulfate, attenuates the development of morphine dependence: an association with sigma1 receptors, 31st Annual Meeting of the Society of Neuroscience (San Diego-November 2001)]. EP1130018 teaches the use of sigma ligands for the treatment of drug addiction to morphine, cocaine and methamphetamine. However, none of these approaches show an enhancement of the analgesic effect of morphine.
Therefore, there is a need to provide new treatments for post-surgical pain which reduce side effects shown by known drugs.